TCGA study of bladder cancer reveals potential drug targets

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted by the disease. They also discovered that, at the molecular level, some subtypes of bladder cancer—also known as urothelial carcinoma—resemble subtypes of breast, head and neck, and lung cancers, suggesting similar routes of development.

The researchers' findings provide important insights into the mechanisms underlying bladder cancer, which is estimated to cause more than 15,000 deaths in the United States in 2014. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.

In this study, published in Nature (2014; doi:10.1038/nature12965), investigators examined bladder cancer that invades the muscle of the bladder, the deadliest form of the disease. The current standard treatments for muscle-invasive bladder cancer include surgery and radiation combined with chemotherapy. There are no recognized second-line therapies—second choices for treatments when the initial therapy does not work—and no approved targeted agents for this type of bladder cancer. Approximately 72,000 new cases of bladder cancer will be diagnosed in the United States in 2014.

"This project has dramatically improved our understanding of the molecular basis of bladder cancers and their relationship to other cancer types," said lead author John Weinstein, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. "In the long run, the potential molecular targets identified may help us to personalize therapy based on the characteristics of each patient's tumor."

"The real excitement about this project is that we now have a menu of treatment and research directions to pursue," said Seth Lerner, MD, of Baylor College of Medicine in Houston, and one of the senior authors of the article. "The field is poised to use this information to make new advances toward therapies for a very difficult to treat form of bladder cancer."

The research team analyzed DNA, RNA, and protein data generated from the study of 131 muscle-invasive bladder cancers from patients who had not yet been treated with chemotherapy, radiation, or any other type of therapy. The scientists found recurrent mutations in 32 genes, including nine that were not previously known to be significantly mutated. Nearly half of the tumor samples had mutations in the TP53, and 44% had mutations and other aberrations in the receptor tyrosine kinase (RTK)/Ras pathway (which is commonly affected in cancers). TP53 makes the p53 tumor-suppressor protein, which helps regulate cell division. RTK/Ras is involved in regulating cell growth and development.

Overall, the researchers identified potential drug targets in 69% of the tumors evaluated. They found frequent mutations in the ERBB2, or HER2, gene. The researchers also identified recurring mutations as well as fusions involving other genes such as FGFR3 and in the PI3-kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.